The optic nerve is an accessible and anatomically simple part of the central nervous system (CNS) that has long been used to investigate the development and regeneration of CNS connections. Like most neurons in the CNS, retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons if injured, resulting in a permanent loss of function. However, if an inflammatory reaction is induced in the eye, injured RGCs revert to an active growth state and begin to extend lengthy axons down the optic nerve. The objectives of this proposal are to understand the molecular mechanisms that underlie this phenomenon and to devise methods to improve functional outcome. In cell culture, macrophages produce a previously unknown growth factor, oncomodulin that can stimulate RGCs to regenerate their axons. However, whether macrophage-derived oncomodulin is actually responsible for stimulating RGCs to regenerate their axons in vivo is unknown, and this will be investigated in Aim 1. Our second aim is to understand how oncomodulin functions at a molecular level. We will investigate whether oncomodulin controls the expression of genes required for axon growth through changes in the expression or activity of specific transcription factors. We will also investigate whether a persistently active form of the protein kinase Mst3b will augment regeneration, and attempt to identify the receptor through which oncomodulin acts. Our third aim is to develop methods to enhance axon regeneration and restore function. We will use gene-therapy approaches to improve oncomodulin delivery, optimize RGC survival, and counteract inhibitory signals associated with myelin and the glial scar, in an effort to get RGCs to regenerate injured axons to the appropriate target areas and restore some level of vision after optic nerve injury. These studies will provide novel insights into the biological mechanisms that underlie regeneration in the optic nerve, and may lead to improved treatments for injuries and degenerative disorders that affect the optic nerve and other CNS pathways. PUBLIC HEALTH RELEVANCE One reason that patients often fail to regain function after spinal cord damage and other types of brain injury is the inability of nerve cells to regenerate injured connections within the central nervous system (CNS). In one widely studied example of this, the projection neurons of the eye normally fail to regenerate their connections if the optic nerve is injured. Surprisingly, recent studies in animals show that if an inflammatory reaction is induced within the eye, the projection neurons of the eye switch into an active growth state and begin to regenerate lengthy axons through the optic nerve. The proposed studies will investigate the molecular mechanisms that underlie this phenomenon and develop therapies to improve outcome. Information gained from these studies is likely to be relevant to treating injury to the optic nerve and other parts of CNS.